Drug addiction is a serious and prolific mental illness involving persistent relapse despite sincere efforts to abstain. This research studies the neurobiological mechanisms underlying sensitization in brain dopamine D2 receptors that would exacerbate drug craving and relapse in cocaine users, and investigates novel approaches to reverse D2 receptor sensitization as potential therapeutic intervention to promote abstinence. Dopamine D2 receptors in the nucleus accumbens (NAc) play a major role in precipitating relapse to cocaine-seeking behavior, and undergo a profound sensitization following chronic cocaine use. Current findings suggest that D2 receptor sensitization is caused by cAMP-PKA up-regulation in NAc neurons, but the mechanism for this effect is unknown. Therefore, Aim I will investigate the effects of chronic cocaine self- administration (SA) in rats on proteins that regulate D2 receptor-G protein coupling, and G protein independent D2 receptor signaling. Studies will also determine whether cocaine regulation is mimicked by cAMP-PKA activation in specific D2-containing NAc cell types. Preliminary data suggest that chronic cocaine SA down- regulates RGS4, a negative regulator of D2 receptor coupling, and Akt phosphorylation, a protein kinase inhibited by G protein-independent D2 receptor signaling. These changes are consistent with an intrinsic mechanism for D2 receptor sensitization. Studies in Aim II will determine the functional contribution of RGS4 and Akt down-regulation to D2 receptor sensitization and the propensity for cocaine-seeking behavior. Studies will utilize highly localized viral-mediated expression systems to study the effects of gain and loss of RGS4 and Akt function in NAc neurons on addictive behavior. These experiments will provide a critical mechanistic link between regulation of these proteins by chronic cocaine SA and the behavioral expression of D2 receptor sensitization. Current studies suggest that a separate extrinsic mechanism also contributes to D2 receptor sensitization, involving cocaine-induced deficits in excitatory AMPA receptor input to NAc neurons. However, extinction of cocaine SA behavior may reverse these deficits by increasing the amount of AMPA receptors, and potentially enhance excitatory AMPA receptor input to NAc neurons. It is hypothesized that extinction training promotes AMPA receptor insertion in synaptic membranes of D2 receptor-containing NAc neurons, and preliminary data show this effect may reverse D2 receptor sensitization and the propensity for cocaine relapse. Aim III will test this hypothesis using biochemical, physiological, and behavioral measures of membrane AMPA receptor expression following extinction training as a potential therapeutic approach to addiction treatment. PUBLIC HEALTH RELEVANCE: Drug addiction is a serious mental illness involving severe motivational disturbances and loss of behavioral control leading to personal devastation. The disease afflicts millions of people with enormous social and economic costs to society. The goal of this research is to better understand the biological basis of the disease, and to identify major biological targets for potential therapeutic intervention to promote abstinence.